1. TMEM16F Forms a Ca2+-Activated Cation Channel Required for Lipid Scrambling in Platelets during Blood Coagulation
- Author
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Yang, Huanghe, Kim, Andrew, David, Tovo, Palmer, Daniel, Jin, Taihao, Tien, Jason, Huang, Fen, Cheng, Tong, Coughlin, Shaun R., Jan, Yuh Nung, and Jan, Lily Yeh
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CALCIUM channels , *BLOOD coagulation , *MEMBRANE lipids , *ASYMMETRY (Chemistry) , *BLOOD platelets , *ELECTROPHYSIOLOGY - Abstract
Summary: Collapse of membrane lipid asymmetry is a hallmark of blood coagulation. TMEM16F of the TMEM16 family that includes TMEM16A/B Ca2+-activated Cl− channels (CaCCs) is linked to Scott syndrome with deficient Ca2+-dependent lipid scrambling. We generated TMEM16F knockout mice that exhibit bleeding defects and protection in an arterial thrombosis model associated with platelet deficiency in Ca2+-dependent phosphatidylserine exposure and procoagulant activity and lack a Ca2+-activated cation current in the platelet precursor megakaryocytes. Heterologous expression of TMEM16F generates a small-conductance Ca2+-activated nonselective cation (SCAN) current with subpicosiemens single-channel conductance rather than a CaCC. TMEM16F-SCAN channels permeate both monovalent and divalent cations, including Ca2+, and exhibit synergistic gating by Ca2+ and voltage. We further pinpointed a residue in the putative pore region important for the cation versus anion selectivity of TMEM16F-SCAN and TMEM16A-CaCC channels. This study thus identifies a Ca2+-activated channel permeable to Ca2+ and critical for Ca2+-dependent scramblase activity during blood coagulation. PaperFlick: Display Omitted [ABSTRACT FROM AUTHOR]
- Published
- 2012
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